Novel guanidino pyridazinones as cardiac stimulants

Abstract

The invention relates to phenyl dihydropyridazinone derivatives that have utility as cardiac stimulants. A compound of the invention is 6-[4-(N 3 -benzyl-N 2 -cyanoguanidino)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone.

What is claimed is: 
     
       1. A compound of the formula (I): ##STR9## or a pharmaceutically acceptable salt thereof wherein: R 1  is hydrogen or methyl; R 2  is C 1-4  alkyl, or C 1-4  alkyl substituted by on or two groups selected from hydroxy, C 1-4  alkoxy, carbamoyl, C 1-4  alkoxycarbonyl and trifluoromethyl, provided that the carbon atom adjacent to the nitrogen atom is not substituted by hydroxy and that no carbon atom is distributed by hydroxy, or --A--R 4  where A is C 1-4  alkylene (straight or branched) and R 4  is phenyl or phenyl substituted by one or two alkoxy, halo, hydroxy, sulfonamido, or trifluoromethyl groups, or is 2-, 3- or 4- pyridyl or 2-benzimidazolyl;   R 3  is cyano, COR 5  or --SO 2  R 6  where R 5  is C 1-4  alkyl, C 1-4  alkoxy or phenyl and R 6  is NHR 7 , C 1-4  alkyl or phenyl; and R 7  is hydrogen or C 1-4  alkyl, R 2  can also be C 3-6  cycloalkyl, alkyl or propargyl when R 3  is cyano; provided that R 2  is not C 1-4  alkyl when R 3  is cyano.   
     
     
       2. A compound according to claim 1 wherein R 1  is methyl. 
     
     
       3. A compound according to claim 1 wherein R 3  is cyano. 
     
     
       4. A compound according to claim 1 wherein R 3  is acetayl, methylsulphonyl or phenylsulphonyl. 
     
     
       5. A compound according to claim 1 wherein R 2  is 2-hydroxyethyl or 2-methoxyethyl. 
     
     
       6. A compound according to claim 1 wherein A is CH 2  or CH 2  CH 2 . 
     
     
       7. A compound according to claim 1 wherein R 4  is phenyl or phenyl substituted by one or two C 1-4  alkoxy halo, hydroxy, sulphonamido or trifluoromethyl groups, or is a 2,3 or 4-pyridyl or 2-benzimidazoyl. 
     
     
       8. A compound according to claim 7 wherein R 4  is phenyl, 4-hydroxyphenyl or 2-pyridyl. 
     
     
       9. A compound according to claim 3 wherein R 2  is cyclopropyl, allyl or propargyl. 
     
     
       10. A compound according to claim 4 wherein R 2  is hydrogen or methyl. 
     
     
       11. A compound according to claim 1 which is: 6-[4-(N 2  -acetylguanidino)phenyl]-5-methyl-4,5-dihydro-(3(2H)-pyridazinone,   6-[4-(N 3  -methyl-N 2  -methylsulphonylguanidino)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone,   6-[4-(N 3  -methyl-N 2  -phenylsulphonylguanidino)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone,   6-[4-(N 3  -(2-methoxyethyl)-N 2  -cyanoguanidino)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone,   6-[4-(N 3  -(2-hydroxyethyl)-N 2  -cyanoguanidino)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone,   6-[4-(N 3  -cyclopropyl-N 2  -cyanoguanidino)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone,   6-[4-(N 3  -allyl-N 2  -cyanoguanidino)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone,   6-[4-(N 3  -propargyl-N 2  -cyanoguanidino)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone,   6-[4-(N 3  -(4-hydroxybenzyl)-N 2  -cyanoguanidino)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone,   6-[4-(N 3  -benzyl-N 2  -cyanoguanidino)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone,   6-[4-(N 3  -(4-methoxybenzyl)-N 2  -cyanoguanidino)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone,   6-[4-(N 3  (2-pyridylmethyl)-N 2  -cyanoguanidino)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone, or   6-[4-(N 3  -phenethyl-N 2  -cyanoguanidino)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone, or   or a pharmaceutically acceptable salt thereof.   
     
     
       12. A compound according to claim 1 which is: 6-[4-(N 3  -methyl-N 2  -phenylsulphonylguanidino)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone, or a pharmaceutically acceptable salt thereof.   
     
     
       13. A compound according to claim 1 which is: 6-[4-(N 3  -benzyl-N 2  -cyanoguanidino)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone, or a pharmaceutically acceptable salt thereof.   
     
     
       14. A compound according to claim 2 in which the (R) isomer is enantiomerically enriched. 
     
     
       15. The (R) isomer of a compound according to claim 2. 
     
     
       16. A pharmaceutical composition having cardiac stimulating activity which comprises an effective amount therefor of a compound according to claim 1 and a pharmaceutically acceptable carrier. 
     
     
       17. A pharmaceutical composition having bronchodilator activity which comprises an effective amount therefor of a compound according to claim 1 and a pharmaceutically acceptable carrier. 
     
     
       18. A pharmaceutical composition having phosphodiesterase (type III) inhibition activity which comprises an effective amount therefor of a compound according to claim 1 and a pharmaceutically acceptable carrier. 
     
     
       19. A pharmaceutical composition according to claim 16 in unit dose form adapted for oral administration. 
     
     
       20. A compound of the formula (IV): ##STR10## wherein: R 1  is hydrogen or methyl, R 3  is COR 5  or SO 2  R 6  where R 5  is C 1-4  alkyl, C 1-4  alkoxy or phenyl and R 6  is NHR 7 , C 1-4  alkyl or phenyl; and R 7  is hydrogen or C 1-4  alkyl; and   L 2  is selected from the group consisting of benzylthio, C 1-6  alkylthio, C 1-6  alkoxy, phenoxy and benzyloxy.